Deletion of FADD in macrophages and granulocytes results in RIP3- and MyD88-dependent systemic inflammation.
Deletion of FADD in macrophages and granulocytes results in RIP3- and MyD88-dependent systemic inflammation.
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巨噬细胞和粒细胞中FADD的缺失导致RIP3-和MYD88依赖性的全身性炎症。
DOI：
10.1371/journal.pone.0124391
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Winoto A
中科院分区：
文献类型：
--
作者：
Schock SN;Young JA;He TH;Sun Y;Winoto A
骨髓细胞包括单核细胞、巨噬细胞和粒细胞，是重要的先天免疫细胞，但其细胞死亡对免疫系统的机制和下游影响尚不完全清楚。坏死性凋亡是细胞死亡的另一种形式，当死亡受体介导的细胞凋亡被阻断时，例如在刺激的Fas相关死亡结构域（FADD）缺陷细胞中，可以触发坏死性凋亡。我们在这里报告，小鼠缺乏FADD在骨髓细胞（mFADD-/-）表现出全身性炎症与升高的炎性细胞因子和增加的水平的骨髓和B细胞群体，而他们的树突状细胞和T细胞数量是正常的。当引入RIP 3缺陷时，这些表型被消除，表明全身性炎症是由RIP 3依赖性坏死性和/或炎症活性引起的。我们进一步发现，MyD 88的缺失可以挽救在这些小鼠中观察到的全身性炎症。这些表型令人惊讶地类似于树突状细胞（DC）特异性FADD缺陷小鼠的表型，除了DC数量在mFADD-/-小鼠中是正常的。这些数据共同支持这样的观点，即先天免疫细胞通过MyD 88依赖性途径不断受到刺激，其细胞死亡机制的畸变可能导致对免疫系统的全身性影响。
Myeloid cells, which include monocytes, macrophages, and granulocytes, are important innate immune cells, but the mechanism and downstream effect of their cell death on the immune system is not completely clear. Necroptosis is an alternate form of cell death that can be triggered when death receptor-mediated apoptosis is blocked, for example, in stimulated Fas-associated Death Domain (FADD) deficient cells. We report here that mice deficient for FADD in myeloid cells (mFADD-/-) exhibit systemic inflammation with elevated inflammatory cytokines and increased levels of myeloid and B cell populations while their dendritic and T cell numbers are normal. These phenotypes were abolished when RIP3 deficiency was introduced, suggesting that systemic inflammation is caused by RIP3-dependent necroptotic and/or inflammatory activity. We further found that loss of MyD88 can rescue the systemic inflammation observed in these mice. These phenotypes are surprisingly similar to that of dendritic cell (DC)-specific FADD deficient mice with the exception that DC numbers are normal in mFADD-/- mice. Together these data support the notion that innate immune cells are constantly being stimulated through the MyD88-dependent pathway and aberrations in their cell death machinery can result in systemic effects on the immune system.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
5.8
作者：
Duprez, Linde;Wirawan, Ellen;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter